Calcium release activated calcium (CRAC) channels are a subset of store-operated channels (SOC) which are opened in response to the depletion of calcium stored in the intracellular endoplasmic reticulum, and are responsible for the entry of extracellular calcium to particular non-excitable cells, particularly, cells of the immune system including T cells and mast cells, and the resulting activation of the cells. Inhibitors of CRAC channel activity are known in the art, and their identification and therapeutic potentials are described by Feske et al. (Non Patent Literature 1 and 2).
Orai1 (CRACM1: calcium release activated calcium modulator 1, transmembrane protein 142A: TMEM142A), a 4-pass transmembrane protein composed of 301 amino acid residues, has been identified as a component constituting the pore forming subunit of CRAC channels by forming a homotetramer (Patent Literature 1 and Non Patent Literature 3 to 5). The Orai gene family comprises the human Orai1 gene together with the human Orai2 and human Orai3 genes which each have 90% or higher homology to the human Orai1 gene (Non Patent Literature 6). In some cases, the possibility of forming a heterotetramer or a heterohexamer containing the Orai2 and/or Orai3 protein and Orai1 has also been reported (Non Patent Literature 7 and 8). Orai1 is constituted by N terminal and C terminal cytoplasmic regions which couple to STIM-1 (stromal interaction molecule 1) or STIM-2, which is a protein sensing the depletion of calcium stored in the intracellular endoplasmic reticulum, and 4 transmembrane domains, the first extracellular loop domain being composed of approximately 20 amino acid residues, and the second extracellular loop domain being composed of approximately 40 amino acid residues (Non Patent Literature 9). The DNA sequence and the amino acid sequence of Orai1 are available on a public database and can be referred to under, for example, Accession Nos. NM_032790 and NP_116179 (NCBI).
It has been found that a congenital defect in the function of the human Orai1 gene eliminates CRAC channel activity and cancels responses of the body to immunogens, resulting in severe immunodeficient conditions. Therefore, the molecular function of Orai1 has been proved essential for the activation of CRAC channels (Non Patent Literature 10 and 11). Thus, function blocking antibodies targeting the Orai1 molecule can serve as inhibitors of CRAC channel activity.
In the light of information suggesting that inhibitors of CRAC channel activity may be used for treating patients with immunological diseases, allergic diseases, inflammatory diseases, transplantation rejection of cells or organs, thrombosis, cancers, etc. (Non Patent Literature 12), attempts have been made to obtain anti-Orai1 antibodies with the aim of inhibiting the molecular function of Orai1, and their effects have been studied (Patent Literature 2 and 3 and Non Patent Literature 13 and 14). Although this literature indicates that each antibody alone inhibits the activation of T cells, the inhibitory activity is not yet sufficiently strong. The clinical application of these antibodies as biologics targeting Orai1 may not satisfy medical needs in terms of the need for high doses or frequent administration, limited administration methods, or the like.